Nonalcoholic fatty liver disease (NAFLD) is currently considered one of the most common chronic liver diseases in the world. NAFLD is defined as the fatty infiltration of the liver without secondary causes such as alcohol, medication, genetic and viral factors. Liver biopsies of patients with NAFLD can range from simple steatosis, which is the presence of increased fat content in the hepatocytes, to steatohepatitis [seen in patients with nonalcoholic steatohepatitis (NASH)] and different stages of hepatic fibrosis, including cirrhosis. It is generally accepted that the NASH subtype of fatty liver is potentially progressive, leading to cirrhosis, liver failure and hepatocellular carcinoma. In fact, presence of fibrosis greater than or equal to stage 2 is independently associated with liver-related mortality.
Because of the rising epidemic of obesity worldwide, NAFLD rates have increased to alarming levels. Although the global prevalence of NAFLD is around 25 percent, this rate varies according to the population under study and the diagnostic modalities used. In this context, there is a great deal of effort to develop and validate noninvasive modalities to identify patients with NASH or significant hepatic fibrosis. Current imaging options, like ultrasound, CT and MRI, are widely used and can establish the presence of hepatic steatosis. However, these modalities fall short in distinguishing different stages of liver damage.
Recently, transient elastography started being used to assess hepatic stiffness. In NAFLD, a number of patient-related factors may reduce its accuracy. Another method is magnetic resonance elastography, which performs better for the evaluation of hepatic parenchyma and assessing various degrees of fibrosis. Although it is highly accurate for detecting liver fibrosis, it is costly, time consuming and not broadly available for general population use. Another recent radiological modality is the liver multiscan study, which also uses MRI mapping techniques to characterize liver tissue at the cellular level. It is a unique method as it can correct the interdependencies caused by increased liver fat, iron load or inflammatory state. The role of these new modalities in clinical practice has yet to be defined.
Of course, these advances are not limited to the radiologic modalities. With the help of advances in biotechnology, scientists have been able to unravel some of the inherited determinants of hepatic steatosis. Like in many other chronic diseases, genetic factors may play an important role in the development and presentation of NAFLD. In this context, the roles of genetic variants have been hypothesized not only in the development of NAFLD, but also in insulin signaling, oxidative stress, fibrogenesis and progression of steatosis to steatohepatitis. For example, genome-wide association studies identified patatin-like phospholipase domaincontaining 3 gene variants, which were the major determinants of inter-individual and ethnicity-related differences in hepatic fat content. Ongoing studies are being carried out to determine the role of these variants and other genomics profiles associated with NAFLD and NASH.
Before discussing treatment, it is important to consider the pathogenesis of NASH. Today we know that obesity and metabolic syndrome are the most important risk factors for the development of NAFLD in the Western world. Nevertheless, it is important to recognize that NAFLD represents a phenotype that can be influenced by a number of other pathogenic pathways. Although deposition of hepatic steatosis may induce the initial step responsible for the first “hit” in the pathogenesis of NASH and related fibrosis, additional “hits” are required to promote liver injury and fibrosis leading to cirrhosis, hepatocellular carcinoma and death. These additional “hits” could be insulin resistance, oxidative stress, imbalance between pro- and anti-inflammatory adipokines-cytokines, endoplasmic reticulum stress, induction of pro-apoptotic pathways and gut dysbiosis. The exact pathway or pathways involved in the development and progression of NASH may vary from patient to patient. This heterogeneity of pathogenic pathways has created a tremendous challenge to developing therapeutic regimens that are effective for all patients with NASH.
For most patients with NASH, lifestyle interventions remain the cornerstone of treatment. The efficacy of lifestyle changes is not only associated with improvements in metabolic control and hepatic histology, but also with potentially improving hepatic fibrosis and even NASH resolution. On the other hand, implementing and maintaining these lifestyle interventions and adherence to the regimens are difficult to achieve in a real-world setting.
In contrast, there are few medical treatment options for NASH. Over the past two decades, pharmacological treatment of NAFLD and NASH has targeted hepatic steatosis, insulin resistance, oxidative stress, hepatic inflammation, hepatocyte apoptosis, gut dysbiosis and hepatic fibrosis, among other pathways. Scientists have tested the efficacy of some anti-diabetic and anti-hyperlipidemic medications, including but not limited to thiazolidinedione, metformin, orlistat, cannabinoid agonists, statins, fibrates and niacin in the management of NAFLD. None of these drugs has shown proven efficacy in NASH. Furthermore, probiotics and ursodeoxycholic acid have been used in patients with NASH without efficacy.
Additionally, glucagon-like peptide-1 agonists like exenatide, dipeptidyl peptidase-4 antagonists like gliptins and sodium-glucose transporter-2 antagonists like gliflozin drugs have been recently developed and are effective medications against hyperglycemia, insulin resistance and hepatic inflammation. Their roles in treatment of NASH remain to be determined. Finally, anti-oxidants such as Vitamin E, Vitamin C, silymarin, betain and zinc have also been tested. Only Vitamin E, which was shown to be effective in non diabetics and non-cirrhotics with NASH, is currently recommended by the American Association for the Study of Liver Diseases Guideline on NAFLD.
Recent studies also emphasized the key role of apoptosis, or controlled cell death, in NAFLD. Researchers have been focusing on caspase inhibitors, peroxisome proliferator-activated receptor alpha and delta agonists, such as elafibranor, and farnesoid-x receptor agonists, which play important roles in bile acid uptake, metabolism and excretion. Simtuzumab, which is a monoclonal antibody against lysyl oxidase-like 2, is also being investigated. These medications are suggested to hold promise, but more research on potential side effects is necessary.
In summary, NAFLD is a liver disease with a global burden that seems to be increasing. It can cause increased mortality and morbidity, and is associated with tremendous costs. Currently, liver biopsy is required for the diagnosis of NASH and provide to the stage of liver disease. However, the era of liver biopsy is rapidly coming to an end as more accurate non invasive biomarkers are being developed. At the moment, lifestyle changes and Vitamin E can be used for some patients with NASH. Although a number of other medications are being considered, their safety and efficacy require robust clinical trials.
Dr. Golabi has no conflicts to disclose.
Dr. Younossi has no conflicts to disclose.